Tacrolimus Education

Tacrolimus (TACR), previously known as FK-506, is a macrocyclic lactone antibiotic that was initially extracted in Japan from the soil microorganism, Streptomyces tsukubaensis, in 1984.1,2 The drug, which is a calcineurin inhibitor, was granted approval by the U.S. Food and Drug Administration (FDA) for preventing rejection after liver (1994), kidney (1997), and heart transplants (2006).1,3

Mechanism of ActionTacrolimus, a potent inhibitor of T-lymphocyte proliferation, binds to the FK-binding protein (FKBP), which is an intracellular cytoplasmic immunophilin.2 The tacrolimus-FKBP complex inhibits the calcium-dependent phosphatase, calcineurin, which leads to the inhibition of T-cell activation, resulting in immunosuppression.2, 4

Clinical IndicationsTACR, which is similar to cyclosporine, but 100 times more potent,5 is mainly indicated for the following:

Prevention of transplant rejection

As a substitute to cyclosporine for primary immunosuppression following solid organ transplantation2

As a rescue therapy in patients with refractory rejection with cyclosporine treatment

Prophylaxis against host-versus-graft disease

Topical therapy for atopic dermatitis, scleroderma, and other eczematous diseases6

Drug InteractionsCYP3A gene and P-glycoprotein play a key role in tacrolimus metabolism. Administration of tacrolimus with other drugs or substances that are also metabolized by the same gene and protein can alter the blood concentrations of the drug.

Dosage and AdministrationTACR is generally administered orally, intravenously, or sublingually.2 The required dose is lower compared to cyclosporine due to its higher potency.4

Monitoring of Tacrolimus LevelsTacrolimus has a low therapeutic index with a high inter-and intra-pharmacokinetic variability, and possesses several side effects and drug interactions.11 All these factors necessitate individualized monitoring of the drug levels in blood. The therapeutic drug monitoring (TDM) methods generally followed include:

Trough concentration (C0) monitoring

Area under the curve (AUC ) monitoring

Monitoring, initiated on the second or third day of therapy, is continued for the first 2 weeks, 3-7 times per week; with a gradual reduction in the monitoring frequency. Some key points to note while monitoring TACR include:12

The cornerstone of TACR evaluation is the trough level obtained 12 hours after the administration of the drug. This measurement provides a good indication of the total drug exposure.13

Studies have found that AUC0-12h correlates well with 12-hour trough levels.4 To overcome the limitations of multiple sampling involved in AUC monitoring, an abbreviated AUC approach has evolved. This involves the evaluation of at least 2 samples collected between 0-4 hours after drug administration.

Enduring Expertise for Your Immunosuppressant Drug Testing Needs

Learn more about the tacrolimus assays available on the following instruments: